Drug eluting implantable medical device with hemocompatible and/or prohealing topcoat

ABSTRACT

The present invention relates to implantable medical devices coated with polymer having hemocompatible and/or prohealing moieties appended thereto and to their use in the treatment of vascular diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 13/453,970 filed on Apr. 23, 2012, which is a divisionalapplication of U.S. patent application Ser. No. 11/881,668 filed on Jul.27, 2007 and entitled “DRUG ELUTING IMPLANTABLE MEDICAL DEVICE WITHHEMOCOMPATIBLE AND/OR PROHEALING TOPCOAT,” which are hereby incorporatedby reference in their entirety.

FIELD OF THE INVENTION

This invention relates to the fields of organic chemistry, polymerscience, material science and medical devices. In particular, it relatesto a medical device having a bioabsorbable coating with hemocompatibleand/or prohealing moieties for treating vascular diseases.

BACKGROUND OF THE INVENTION

Percutaneous transluminal coronary angioplasty (PTCA) is a commonprocedure for treating heart disease. A problem associated with the PTCAincludes the formation of intimal flaps or torn arterial linings whichcan collapse and occlude the conduit after the balloon is deflated.Moreover, thrombosis and restenosis of the artery may develop overseveral months after the procedure, which may require anotherangioplasty procedure or a surgical by-pass operation. To reduce thepartial or total occlusion of the artery by the collapse of arteriallining, and to reduce the chance of the development of thrombosis andrestenosis, a stent may be implanted in the lumen to maintain thevascular patency.

Stents are used not only as a mechanical intervention but also as avehicle for providing biological therapy. As a mechanical intervention,stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Biological therapy can beachieved by medicating the stents, in particular by using drug-elutingstents, DESs. DESs can provide local administration of a therapeuticsubstance at the specific site in an patient's body. This can result infewer and less severe side effects and more favorable overall results.

The early use of coronary stents to improve the long-term patency of anartery post-angioplasty was, however, complicated by a high incidence ofsubacute thrombosis (SAT) (R. A. Schatz et al., Circulation 1991, 83:148-161). Despite improved pharmacological control of SAT, the potentialfor stent occlusion remains a serious problem. In addition, with theadvent of DESs a new problem arose: late stent thrombosis, the formingof blood clots long after the stent is in place. It was deduced that theformation of blood clots was most likely due to delayed healing whichwas postulated to be a side-effect of the use of cytostatic drugs.

Delayed healing and polymer degradation have also been associated withstent malposition, and hypersensitivity reactions.

What is needed is an implantable medical device that has improvedhemocompatibility and/or prohealing properties to ameliorate, if noteliminate, subacute thrombosis, late stent thrombosis and other problemsassociated with delayed healing. The current invention provides suchimplantable medical devices.

SUMMARY OF THE INVENTION

Thus, in one aspect, the current invention relates to an implantablemedical device, comprising:

a device body;an optional primer layer disposed over the device body;a drug reservoir layer disposed over the device body or the primerlayer, if opted,wherein the drug reservoir layer comprises:

-   -   a high molecular weight copolymer of lactic acid, L-lactide,        D,L-lactide or meso-lactide with ε-caprolactone or trimethylene        carbonate, at least a portion of which is substituted with a        hemocompatible and/or prohealing moiety; or,    -   a blend of a high molecular weight copolymer of lactic acid,        L-lactide, D,L-lactide or meso-lactide with ε-caprolactone or        trimethylene carbonate with a low molecular weight copolymer of        lactic acid, L-lactide, D,L-lactide or meso-lactide with        ε-caprolactone or trimethylene carbonate at least a portion of        which is substituted with a hemocompatible and/or prohealing        moiety; or, a high molecular weight copolymer of lactic acid,        L-lactide, D,L-lactide or meso-lactide with ε-caprolactone or        derivatives thereof; and,    -   one or more therapeutic agents, wherein:        -   if the drug reservoir layer comprises only a high molecular            weight copolymer of lactic acid, L-lactide, D,L-lactide or            meso-lactide with ε-caprolactone or trimethylene carbonate,            the implantable medical device further comprises a topcoat            layer comprising a low molecular weight copolymer of lactic            acid, L-lactide, D,L-lactide or meso-lactide with            ε-caprolactone or trimethylene carbonate at least a portion            of which is substituted with a hemocompatible and/or            prohealing moiety.

In an aspect of this invention, the implantable medical device is astent.

In an aspect of this invention, the hemocompatible and/or prohealingmoiety comprises a polyhydroxyalkyl.

In an aspect of this invention, the drug reservoir layer or the topcoatlayer comprises a polyhydroxyalkyl moiety having the formula:

wherein L comprises a Linker; m and n have values from 0 to 1, whereinm+n=1; and p is an integer from 1 to 200.

In an aspect of this invention, the polyhydroxyalkyl is selected fromthe group consisting of glycerol, sorbitol, mannitol, a glycol, apolyalkylglycol and a polyglycol.

In an aspect of this invention, the hemocompatible and/or prohealingmoiety comprises a peptide.

In an aspect of this invention, the drug reservoir layer or the topcoatlayer comprises a peptide moiety having the formula:

wherein L comprises a Linker and m and n have values from 0 to 1 whereinm+n=1.

In an aspect of this invention, the peptide is selected from the groupconsisting of RGD, cyclic RGD (cRGD) and an RDG mimetic.

In an aspect of this invention the hemocompatible and/or prohealingmoiety comprises a phosphorylcholine.

In an aspect of this invention, the drug reservoir layer or the topcoatlayer comprises a phosphorylcholine moiety having the formula:

wherein L comprises a Linker and m and n have values from 0 to 1 suchthat m+n=1.

In an aspect of this invention, the drug reservoir layer polymer has amolecular weight from about 50,000 to about 500,000 Daltons.

In an aspect of this invention, the drug reservoir layer has a coatingthickness from about 1 um to about 10 um.

In an aspect of this invention, the drug to polymer wt/wt ratio in thedrug reservoir layer is from about 1.0:0.5 to about 1.0:10.0.

In an aspect of this invention, the drug dose is from about 5-200microgram/cm² to about 20-100 microgram/cm².

An aspect of this invention is a method of treating a vascular disease,comprising: deploying in the vasculature of a patient in need thereof animplantable medical device,

wherein the device comprises:

a device body;an optional primer layer disposed over the device body;a drug reservoir layer disposed over the device body or the primerlayer, if opted,wherein the drug reservoir layer comprises:

-   -   a high molecular weight copolymer of lactic acid, L-lactide,        D,L-lactide or meso-lactide with ε-caprolactone or trimethylene        carbonate, at least a portion of which is substituted with a        hemocompatible and/or prohealing moiety; or,    -   a blend of a high molecular weight copolymer of lactic acid,        L-lactide, D,L-lactide or meso-lactide with ε-caprolactone or        trimethylene carbonate and a low molecular weight copolymer of        lactic acid, L-lactide, D,L-lactide or meso-lactide with        ε-caprolactone or trimethylene carbonate at least a portion of        which is substituted with a hemocompatible and/or prohealing        moiety; or, a high molecular weight copolymer of lactic acid,        L-lactide, D,L-lactide or meso-lactide with ε-caprolactone or        trimethylene carbonate; and one or more therapeutic agents,        wherein:    -   if the drug reservoir layer comprises only a high molecular        weight copolymer of lactic acid, L-lactide, D,L-lactide or        meso-lactide with ε-caprolactone or trimethylene carbonate, the        implantable medical device further has a topcoat layer        comprising a low molecular weight copolymer of lactic acid,        L-lactide, D,L-lactide or meso-lactide with ε-caprolactone or        trimethylene carbonate at least a portion of which is        substituted with hemocompatible and/or prohealing moiety.

In an aspect of this invention, the implantable medical device is astent.

In an aspect of this invention, the hemocompatible and/or prohealingmoiety comprises a polyhydroxyalkyl.

In an aspect of this invention, the drug reservoir layer or the topcoatlayer comprises a polyhydroxyalkyl moiety having the formula:

wherein L comprises a Linker, m and n have values from 0 to 1 such thatm=n=1 and p is an integer from 1 to about 200.

In an aspect of this invention, the polyhydroxyalkyl is selected fromthe group consisting of glycerol, sorbitol, mannitol, a glycol, apolyalkylglycol and a polyglycol.

In an aspect of this invention, the hemocompatible and/or prohealingmoiety comprises a peptide.

In an aspect of this invention, the drug reservoir layer or the topcoatlayer comprises a peptide moiety having the formula:

wherein L comprises a Linker and m and n have values from 0 to 1 suchthat m+n=1

In an aspect of this invention, the peptide is selected from the groupconsisting of RGD, cyclic RGD (cRGD) and an RDG mimetic.

In an aspect of this invention, the hemocompatible and/or prohealingmoiety comprises a phosphorylcholine.

In an aspect of this invention, the drug reservoir layer or the topcoatlayer comprises a phosphorylcholine moiety having the formula:

wherein L comprises a Linker and m and n have values from 0 to 1 suchthat m+n=1.

In an aspect of this invention, the drug reservoir layer polymer has amolecular weight from about 50,000 to about 500,000 Daltons.

In an aspect of this invention, the drug reservoir layer has a coatingthickness from about 1 um to about 10 um.

In an aspect of this invention, the drug to polymer wt/wt ratio in thedrug reservoir layer is from about 1.0:0.5 to about 1.0:10.0.

In an aspect of this invention, the drug dose is from about 5-200microgram/cm² to about 20-100 microgram/cm².

In an aspect of this invention, the vascular disease is atherosclerosis.

In an aspect of this invention, the vascular disease is restenosis.

In an aspect of this invention, the vascular disease is vulnerableplaque

In an aspect of this invention, the vascular disease is peripheralvascular disease.

In an aspect of this invention, the vascular disease is late stentthrombosis.

DETAILED DESCRIPTION OF THE INVENTION

Use of the singular herein includes the plural and visa versa unlessexpressly stated to be otherwise. That is, “a” and “the” refer to one ormore of whatever the word modifies. For example, “a therapeutic agent”includes one such agent, two such agents, etc. Likewise, “the layer” mayrefer to one, two or more layers and “the polymer” may mean one polymeror a plurality of polymers. By the same token, words such as, withoutlimitation, “layers” and “polymers” would refer to one layer or polymeras well as to a plurality of layers or polymers unless, again, it isexpressly stated or obvious from the context that such is not intended.

As used herein, an “implantable medical device” refers to any type ofappliance that is totally or partly introduced, surgically or medically,into a patient's body or by medical intervention into a natural orifice,and which is intended to remain there after the procedure. The durationof implantation may be essentially permanent, i.e., intended to remainin place for the remaining lifespan of the patient; until the devicebiodegrades; or until it is physically removed. Examples of implantablemedical devices include, without limitation, implantable cardiacpacemakers and defibrillators; leads and electrodes for the preceding;implantable organ stimulators such as nerve, bladder, sphincter anddiaphragm stimulators, cochlear implants; prostheses, vascular grafts,self-expandable stents, balloon-expandable stents, stent-grafts, grafts,artificial heart valves and cerebrospinal fluid shunts.

An implantable medical device specifically designed and intended solelyfor the localized delivery of a therapeutic agent is within the scope ofthis invention.

As used herein, “device body” refers to a fully formed implantablemedical with an outer surface to which no coating or layer of materialdifferent from that of which the device itself is manufactured has beenapplied. By “outer surface” is meant any surface however spatiallyoriented that is in contact with bodily tissue or fluids. A commonexample of a “device body” is a BMS, i.e., a bare metal stent, which, asthe name implies, is a fully-formed usable stent that has not beencoated with a layer of any material different from the metal of which itis made on any surface that is in contact with bodily tissue or fluids.Of course, device body refers not only to BMSs but to any uncoateddevice regardless of what material it is made.

Implantable medical devices made of virtually any material, i.e.,materials presently known to be useful for the manufacture ofimplantable medical devices and materials that may be found to be so inthe future, may be used with a coating of this invention. For example,without limitation, an implantable medical device useful with thisinvention may be made of one or more biocompatible metals or alloysthereof including, but not limited to, cobalt-chromium alloy (ELGILOY,L-605), cobalt-nickel alloy (MP-35N), 316L stainless steel, highnitrogen stainless steel, e.g., BIODUR 108, nickel-titanium alloy(NITINOL), tantalum, platinum, platinum-iridium alloy, gold andcombinations thereof.

Implantable medical devices may also be made of polymers that arebiocompatible and biostable or biodegradable, the latter term includingbioabsorbable and/or bioerodable.

As used herein, “biocompatible” refers to a polymer that both in itsintact, as synthesized state and in its decomposed state, i.e., itsdegradation products, is not, or at least is minimally, toxic to livingtissue; does not, or at least minimally and reparably, injure livingtissue; and does not, or at least minimally and/or controllably, causean immunological reaction in living tissue.

Among useful biocompatible, relatively biostable polymers are, withoutlimitation, polyacrylates, polymethacryates, polyureas, polyurethanes,polyolefins, polyvinylhalides, polyvinylidenehalides, polyvinylethers,polyvinylaromatics, polyvinylesters, polyacrylonitriles, alkyd resins,polysiloxanes and epoxy resins.

Biocompatible, biodegradable polymers include naturally-occurringpolymers such as, without limitation, collagen, chitosan, alginate,fibrin, fibrinogen, cellulosics, starches, dextran, dextrin, hyaluronicacid, heparin, glycosaminoglycans, polysaccharides and elastin.

One or more synthetic or semi-synthetic biocompatible, biodegradablepolymers may also be used to fabricate an implantable medical deviceuseful with this invention. As used herein, a synthetic polymer refersto one that is created wholly in the laboratory while a semi-syntheticpolymer refers to a naturally-occurring polymer than has been chemicallymodified in the laboratory. Examples of synthetic polymers include,without limitation, polyphosphazines, polyphosphoesters,polyphosphoester urethane, polyhydroxyacids, polyhydroxyalkanoates,polyanhydrides, polyesters, polyorthoesters, polyamino acids,polyoxymethylenes, poly(ester-amides) and polyimides.

Blends and copolymers of the above polymers may also be used and arewithin the scope of this invention. Based on the disclosures herein,those skilled in the art will recognize those implantable medicaldevices and those materials from which they may be fabricated that willbe useful with the coatings of this invention.

At present, preferred implantable medical devices for use with thecoatings of this invention are stents.

A stent refers generally to any device used to hold tissue in place in apatient's body. Particularly useful stents, however, are those used forthe maintenance of the patency of a vessel in a patient's body when thevessel is narrowed or closed due to diseases or disorders including,without limitation, tumors (in, for example, bile ducts, the esophagus,the trachea/bronchi, etc.), benign pancreatic disease, coronary arterydisease, carotid artery disease and peripheral arterial disease such asatherosclerosis, restenosis and vulnerable plaque. Vulnerable plaque(VP) refers to a fatty build-up in an arterial wall thought to be causedby inflammation. The VP is covered by a thin fibrous cap that canrupture leading to blood clot formation. A stent can be used tostrengthen the wall of the vessel in the vicinity of the VP and act as ashield against such rupture. A stent can be used in, without limitation,neuro, carotid, coronary, pulmonary, aorta, renal, biliary, iliac,femoral and popliteal as well as other peripheral vasculatures. A stentcan be used in the treatment or prevention of disorders such as, withoutlimitation, thrombosis, restenosis, hemorrhage, vascular dissection orperforation, vascular aneurysm, chronic total occlusion, claudication,anastomotic proliferation, bile duct obstruction and ureter obstruction.

In addition to the above uses, stents may also be employed for thelocalized delivery of therapeutic agents to specific treatment sites ina patient's body. In fact, therapeutic agent delivery may be the solepurpose of the stent or the stent may be primarily intended for anotheruse such as those discussed above with drug delivery providing anancillary benefit.

A stent used for patency maintenance is usually delivered to the targetsite in a compressed state and then expanded to fit the vessel intowhich it has been inserted. Once at a target location, a stent may beself-expandable or balloon expandable. In any event, due to theexpansion of the stent, any coating thereon must be flexible and capableof elongation.

As used herein, “optional” means that the element modified by the termmay or may not be present. For example, without limitation, a devicebody (db) that has coated on it an “optional” primer layer (pl), a drugreservoir layer (dr), and an “optional” top-coat layer (tc) refers,without limitation, to any of the following devices: db+dr, db+pl+dr,db+dr+tc, and db+pl+dr+tc.

As used herein, a “primer layer” refers to a coating consisting of apolymer or blend of polymers that exhibit good adhesion characteristicswith regard to the material of which the device body is manufactured andgood adhesion characteristic with regard to whatever material is to becoated on the device body. Thus, a primer layer serves as anintermediary layer between a device body and materials to be affixed tothe device body and is, therefore, applied directly to the device body.Examples without limitation, of primers include acrylate andmethacrylate polymers with poly(n-butyl methacrylate) being a presentlypreferred primer. Some additional examples of primers include, but arenot limited to, poly(ethylene-co-vinyl alcohol), poly(vinylacetate-co-vinyl alcohol), poly(methacrylates), poly(acrylates),polyethyleneamine, polyallylamine, chitosan, poly(ethylene-co-vinylacetate), and parylene-C.

As use herein, a material that is described as a layer “disposed over”an indicated substrate, e.g., without limitation, a device body oranother layer, refers to a relatively thin coating of the materialapplied, preferably at present, directly to essentially the entireexposed surface of the indicated substrate. By “exposed surface” ismeant that surface of the substrate that, in use, would be in contactwith bodily tissues or fluids. “Disposed over” may, however, also referto the application of the thin layer of material to an intervening layerthat has been applied to the substrate, wherein the material is appliedin such a manner that, were the intervening layer not present, thematerial would cover substantially the entire exposed surface of thesubstrate.

As used herein, “drug reservoir layer” refers either to a layer of oneor more therapeutic agents applied neat or to a layer of polymer orblend of polymers that has dispersed within its three-dimensionalstructure one or more therapeutic agents. A polymeric drug reservoirlayer is designed such that, by one mechanism or another, e.g., withoutlimitation, by elution or as the result of biodegradation of thepolymer, the therapeutic substance is released from the layer into thesurrounding environment. For the purpose of this invention, the drugreservoir layer also acts as rate-controlling layer. As used herein,“rate-controlling layer” refers to a polymer layer that controls therelease of therapeutic agents or drugs into the environment. While anypolymer may be used to construct a drug reservoir layer of thisinvention, in particular when a topcoat layer comprising hemocompatibleand/or pro-healing moieties is used, in presently preferred embodimentsof this invention, the drug reservoir layer comprises a high molecularweight copolymer of lactic acid, L-lactide, D,L-lactide or meso-lactidewith ε-caprolactone or derivatives thereof, at least a portion of whichis substituted with a hemocompatible and/or prohealing moiety; or, ablend of a high molecular weight copolymer of lactic acid, L-lactide,D,L-lactide or meso-lactide with ε-caprolactone or trimethylenecarbonate with a low molecular weight copolymer of lactic acid,L-lactide, D,L-lactide or meso-lactide with ε-caprolactone ortrimethylene carbonate at least a portion of which is substituted with ahemocompatible and/or prohealing moiety; or, a high molecular weightcopolymer of lactic acid, L-lactide, D,L-lactide or meso-lactide withε-caprolactone or derivatives thereof.

It is understood that many other biocompatible, hydrophobic polymerscapable of being modified with hemocompatible and/or pro-healingmoieties can be used as drug reservoir and/or topcoat layers of thisinvention. All such polymers are within the scope of this invention, thesalient aspect of which is in fact the inclusion of the hemocompatibleand/or pro-healing moieties in the outermost layer of the coating on animplantable medical device whether it be the drug reservoir layer, aseparate rate-controlling layer or a topcoat layer.

As used herein, “hydrophobic” refers to a polymer that lacks an affinityfor water. That is, it tends to repel water, to not dissolve in, mixwith or be wetted by water or to do so only to a very limited degree andto not absorb water or, again, to do so only to a very limited degree.With regard to polymers, generally hydrophobicity increase withincreasing alkyl content in the polymer backbone, that is, the greaterthe alkyl content in one or more of the constitutional units of thepolymer. The hydrophobicity of a polymer may be characterized bydetermining the static contact angle of droplets of distilled water on asurface of the polymer. The greater the contact angle, the morehydrophobic the polymer. Generally speaking, a contact angle of greaterthan 90° indicates a hydrophobic polymer. The specifics or suchmeasurements will not be presented here since they are well-known tothose skilled in the art.

As used herein, “contact angle” is defined as an angle at the tangent ofa droplet in a fluid phase that has taken an equilibrium shape on asolid surface under ambient condition.

As used herein, “hydrophobicity” can be gauged using the Hildebrandsolubility parameter δ. The term “Hildebrand solubility parameter”refers to a parameter indicating the cohesive energy density of asubstance. The δ parameter is determined as follows:

δ=(ΔE/V)^(1/2)

where δ is the solubility parameter, (cal/cm³)^(1/2);ΔE is the energy of vaporization, cal/mole; andV is the molar volume, cm³/mole.

Accordingly, for the practice of the present invention, whether amaterial is hydrophobic or hydrophilic is relative. Between differentmaterials, whichever has a lower Hildebrand value (δ) value compared tothe δ value of the other is designated as a hydrophobic, and thematerial with higher Hildebrand value (δ) value is designated as ahydrophilic. In one embodiment, the δ value defining the boundarybetween hydrophobic and hydrophilic can be between about 9.9 and 10.1(cal/cm³)^(1/2). According to this embodiment, hydrophobic is defined ashaving a δ value equal to or below about 9.9 (cal/cm³)^(1/2), andhydrophilic is defined as having a δ value of about 10.1 (cal/cm³)^(1/2)or higher. Materials having a δ value between about 9.9 and 10.1(cal/cm³)^(1/2) can exhibit behavior characterized by both hydrophilicand hydrophobic materials. Such materials are defined as “amphiphilic.”Measurements other than Hildebrand value for the determination ofhydrophobicity are known to those skilled in the art and may be employedin the same manner as the Hildebrand value to achieve the same end.

Suitable hydrophobic polymers include, without limitation, poly(vinylacetate), poly(ethylene-co-vinyl acetate), poly(vinyl acetals) such aspoly(vinyl butyral) (e.g., BUTVAR), poly(meth)acrylates, for example,poly(methyl methacrylate), poly(ethyl methacrylate), poly(n-propylmethacrylate), poly(iso-propyl methacrylate), poly(n-butylmethacrylate), copolymers of butyl n-methacrylate with non-polarmonomers (e.g., poly(ethyl methacrylate-co-n-butyl methacrylate)),poly(iso-butyl methacrylate), poly(methyl acrylate), poly(ethylacrylate), poly(n-propyl acrylate), poly(iso-propyl acrylate),poly(n-butyl acrylate), poly(iso-butyl acrylate),styrene-butadiene-styrene triblock copolymers,styrene-ethylene/butylene-styrene triblock copolymers (e.g., KRATONavailable from Shell Oil Co. of Houston, Tex.),styrene-isobutylene-styrene triblock copolymers, parylene-C,organosilicon polymers (e.g., ELASTEON), and halogenated (e.g.,fluorinated or chlorinated) polymers such as poly(vinyl chloride),poly(vinyl fluoride), poly(vinylidene chloride), poly(vinylidenefluoride) (e.g., KYNAR available from Atofina Chemicals, Inc. ofPhiladelphia, Pa.), poly(hexafluoropropene), poly(vinylidenefluoride-co-hexafluoropropene) (e.g., SOLEF available from Solvay S.A.of Brussels, Belgium), poly(ethylene-co-hexafluoropropene), and variousgrades of amorphous TEFLON, including polytetrafluoroethylene (availablefrom E.I. Du Pont de Nemours & Co. of Wilmington, Del.), BUTVAR is atrade name of poly(vinyl butyral) (available from Solutia, Inc. of St.Louis, Mo.), ELASTEON is the trade name of the block copolymer ofmethylene diphenyl diisocyanate, 1,4-butanediol,polyhexamethyleneglycol, and a carbinol terminated polydimethylsiloxane(manufactured by AorTech Biomaterials Co. of Chatswood, Australia),poly[trimellitylimido-L-tyrosine-co-sebacicacid-co-1,3-bis(para-carboxyphenoxy)propane] p(TMIT-SBA-PCPP),poly[1,6-bis(para-carboxyphenoxy)-hexane-co-di-ortho-carboxyphenoxysebacateanhydride] p(PCPX-OCPSA), poly[1,3-bis(para-carboxyphenoxy)propane-co-salicylic acid-co-sebacic acid] p(PCPP-SBA-SA), poly(maleicacid-co-sebacic acid), p(MA-SBA), poly(L-lactic acid-co-L-asparticacid), p(LLA-LAspA), poly(DL-lactic acid-co-L-aspartic acid)p(DLLA-LAspA), poly(L-lactic acid) pLLA, poly(DL-lactic acid) pDLLA,poly(L-lactic acid-co-ethylene glycol) p(LLA-EG), poly(DL-lacticacid-co-ethylene glycol) p(DLLA-EG), poly(ethylene glycol-co-butyleneterephthalate) p(EG-BT), poly(4-hydroxy-L-proline ester) p(HOXPE),poly(1,10-decanediol-co-L-lactic acid) p(DCD-LLA),poly(1,10-decanodiol-co-D,L-lactic acid) p(DCD-DLLA),poly(1,2,6-hexanetriol-co-trimethylorthoacetate) p(HTOL-TMAC),poly(hydroxybutyrate) (PHB), poly(hydroxyvalerate) (PHV),poly(hydroxy-butyrate-valerate) (PHBV),poly(L-lactide-co-ε-caprolactone) and poly(L-lactide-co-trimethylenecarbonate).

As used herein, “hemocompatible” refers to a property of a surface of adevice to cause little, preferably no, harm to blood or bloodcomponents. In general, the tests set forth in ISO (internationalOrganization for Standardization) 10993 may be employed to ascertain thelevel of hemocompatibility of a particular device of this invention.

As used herein, “prohealing” refers to a moiety that aids in the healingprocess at the site of implantation of a medical device of thisinvention. Useful pro-healing moieties include, without limitation,endothelial progenitor cells, nitric oxide, vascular endothelial growthand 17-b-estradiol.

As used herein, any words of approximation such as without limitation,“about,” “essentially,” “substantially” and the like mean that theelement so modified need not be exactly that which is modified by theterm but which would still be considered by one of ordinary skill in theart to be recognizable as that element. In general, for the purpose ofthis invention, this means that an element so modified can vary from thedescription by at least ±15% without exceeding the scope of thisinvention.

As used herein, the term “constitutional unit” refers to the repeatingunits that make up the polymer. For example, in thepoly(L-lactide-co-ε-caprolactone) of this invention the constitutionalunits are —OCH(CH₃)C(═O)—, derived from L-lactide and —O(CH₂)₅C(═O)—,derived from ε-caprolactone. For the purposes of this invention theconstitutional unit wt/wt ratio of a presently preferred polymer is fromabout 70:30 to about 50:50.

As used herein, “Linker” refers to a multifunctional moiety in which atleast one functional group is capable of reacting with a functionalgroup on the backbone of a polymer hereof and a different functionalgroup capable of reacting with a functional group on a hemocompatibleand/or pro-healing moiety so as to join or ‘link” the hemocompatibleand/or prohealing group(s) to the polymer backbone.

As used herein, “and/or” in the phrase “hemocompatible and/orpro-healing” refers to either a chemical moiety that possesses bothproperties or to individual moieties that exhibit one or the otherproperty. With regard to a hemocompatible and/or pro-healing polymer ofthis invention, the polymer may have the chemical moiety possessing bothproperties appended to its backbone, it may have an individual moietyexhibiting one of the properties appended to its backbone, it may havetwo different moieties, one possessing one of the properties and thesecond possessing the other property both appended to its backbone orany combination of the foregoing.

As used herein [[—Y—]_(n)/[—Z—]_(m)]_(x) refers to a random, a regularalternating or a block, preferably at present a random, copolymer. Asuse herein, the letters “n” and “m” connote mole fractions of theconstitutional units Y and Z, that is, m and n each have values from 0to 1 such that m+n=1, where m is from about 0.01 to about 0.99 and n isfrom about 0.99 to about 0.01. It is presently preferred that m is fromabout 0.5 to about 0.8. It is most presently preferred that the m isfrom about 0.65 to about 0.75. The letter “x” connotes sequencemultiplicity, that is, the number of repeats of the entity within theoutside brackets in the polymer.

As used herein, a “topcoat layer” refers to an outermost layer, that is,a layer that is in contact with the external environment and that iscoated over all other layers. The topcoat layer may be a separate layerdistinct from drug reservoir layer or the drug reservoir layer mayitself be the outermost layer and therefore constitute the topcoat layerof a coating, if the drug reservoir layer contains hemocompatible and/orprohealing moieties. A separate topcoat layer may be applied to providebetter hydrophilicity to the device, to better lubricate the device ormerely as a physical protectant of the underlying layers. If the drugreservoir layer comprises a high molecular weight copolymer of lacticacid, L-lactide, D,L-lactide or meso-lactide with ε-caprolactone orderivatives thereof, the implantable medical device further has atopcoat layer comprising a low molecular weight copolymer of lacticacid, L-lactide, D,L-lactide or meso-lactide with ε-caprolactone ortrimethylene carbonate at least a portion of which is substituted with ahemocompatible and/or prohealing moiety. For the purposes of thisinvention, the outermost layer, be it the drug reservoir or the topcoatlayer must comprises a hemocompatible and/or prohealing moiety. In apresently preferred embodiment, the hemocompatible and/or prohealingmoiety comprises polyhydroxyalkyl, phosphoryl-choline and/or peptides.Other natural or recombinant polymers can also provide prohealingproperties which include, but not limited to, elastin, collagen,laminin, and polysaccharide.

Presently preferred polymers used to construct either a drug reservoirlayer or a topcoat layer of this invention, include, but not limited to,polymers having a hydrophobic polymer backbone with hydrophilic,hemocompatible and/or prohealing pendant groups. The presentlypreferable polymer used to construct hydrophobic polymer backbone ofthis invention is a copolymer comprising at least two monomers one ofwhich is selected from the group consisting of L-lactide, D-lactide,D,L-lactide and meso-lactide. The second monomer selected from the groupconsisting of lactone, ε-caprolactone, δ-valerolactone,1,4-dioxan-2-one, 1,5-dioxepan-2-one, 1,4,6-trioxaspiro[4.4]nonane andtrimethyl carbonate. Presently preferred hydrophobic polymer backbone ofthis invention are poly(L-lactide-co-ε-caprolactone) andpoly(L-lactide-co-trimethylene carbonate).

The combination of biocompatibility and biodegradability with thephysical strength provided by poly(L-lactide-co-ε-caprolactone) isuseful for medical device application. However, the simplicity of thepolymer presents limitations in terms of functionality and physicalproperties, mainly because of its hydrophobic nature. Branching andpendant functionalization of hydrophobic polymers provides a uniqueopportunity to alter physical and chemical properties by distributingfunctionality along the polymer backbone. Pendant functionalization ofthe polymers can be achieved by polymerization of functionalizedlactones or post polymerization modification or a combination of thesetwo methods. Branching and/or pendant functionality can be used to tunephysical and chemical properties, including viscosity, solubility,hydrophilicity, adhesion and blood compatibility. The hydrophobicpolymers can be modified to have pendant groups which are hydrophilic.These hydrophilic groups are hemocompatible and/or prohealing moieties.Suitable hydrophilic, hemocompatible and/or prohealing moieties include,without limitation, polyhydroxyalkyl, phosphorylcholine, and peptides.

Suitable examples of polyhydroxyalkyls include, without limitation,glycerol, sorbitol, mannitol, a glycol, a polyalkylglycol and apolyglycol.

An advantage of having phosphoryl choline (PC) as the hemocompatible andpro-healing moiety lies in its surface chemistry. That is, PC has azwitterionic functionality that mimics the outer blood-contactingsurface of the lipid bilayer structure in blood corpuscles. PC possessesnumerous beneficial properties such as hemocompatibility and/orprohealing characteristics, non-thrombogenicity, arterial tissueacceptance and long-term in vivo stability. PC-containing polymers areextremely hydrophilic and associate a large number of water moleculesbecause of the zwitterionic nature of the PC head group. Further,coatings comprising PC-containing polymers in the outermost layer tendto not invoke adverse inflammatory response.

The polypeptide Arg-Gly-Asp (RGD) has been demonstrated to be abioactive factor for human endothelial cell attachment and therefore isexpected to exhibit prohealing characteristics. In addition to RGDitself, cyclic RGD (cRGD) and RGD mimetics and small molecules capableof binding as does RGD to other adhesion receptors differentiallyexpressed on the endothelial cells are within the scope of thisinvention. RGD mimetics can be prepared, without limitation bymodification of RGD or cRGD. Peptide synthesis including the synthesisof peptide mimetics, is well documented and can be readily achievedusing, for example, combinatorial chemistry. Some examples of cRGD orRGD mimetics include V₃ antagonists such as IIb/IIIb antagonists (B. S.Coller, Thromb. Haemost. 2001, 86:427-443 (Review)), one example ofwhich is Abciximax (R. Blindt, J. Mol. Cell. Cardiol. 2000,32:2195-2206), XJ 735 (S. S. Srivastva et al., Cardiovasc. Res. 1997,36:408-428), anti-₃-integrin antibody F11, cRGD (M. Sajid et al., Am. J.Physiol. Cell Physiol., 2003, 285:C1330-1338), and other sequences suchas laminin derived SIKVAV (M. H. Fittkau et al., Biomaterials, 2005,26:167-174), laminin derived YIGSR(S. Kouvroukoglou et al.,Biomaterials, 2000, 21:1725-1733), KQAGDV, and VAPG (B. K. Mann, B. K.,J. Biomed. Mater. Res. 2002, 60:86-93).

The presently preferable polymers of this invention to whichhemocompatible and/or prohealing moieties can be appended arepoly(L-lactide-co-ε-caprolactone) and poly(L-lactide-co-trimethylenecarbonate). The presently preferable hydrophilic, hemocompatible and/orprohealing moieties used in this invention are polyhydroxyalkyl,phosphorylcholine, and peptides.

In addition to the comprising a polymer having hemocompatible and/orpro-healing properties, a coating on an implantable medical device ofthis invention may also contain in the drug reservoir layer and possiblyin the topcoat layer one or more therapeutic agents.

As used herein, “therapeutic agent” refers to any substance that, whenadministered in a therapeutically effective amount to a patientsuffering from a disease, has a therapeutic beneficial effect on thehealth and well-being of the patient. A therapeutic beneficial effect onthe health and well-being of a patient includes, but it not limited to:(1) curing the disease; (2) slowing the progress of the disease; (3)causing the disease to retrogress; or, (4) alleviating one or moresymptoms of the disease. As used herein, a therapeutic agent alsoincludes any substance that when administered to a patient, known orsuspected of being particularly susceptible to a disease, in aprophylactically effective amount, has a prophylactic beneficial effecton the health and well-being of the patient. A prophylactic beneficialeffect on the health and well-being of a patient includes, but is notlimited to: (1) preventing or delaying on-set of the disease in thefirst place; (2) maintaining a disease at a retrogressed level once suchlevel has been achieved by a therapeutically effective amount of asubstance, which may be the same as or different from the substance usedin a prophylactically effective amount; or, (3) preventing or delayingrecurrence of the disease after a course of treatment with atherapeutically effective amount of a substance, which may be the sameas or different from the substance used in a prophylactically effectiveamount, has concluded.

As used herein, the terms “drug” and “therapeutic agent” are usedinterchangeably.

As used herein, “treating” refers to the administration of atherapeutically effective amount of a therapeutic agent to a patientknown or suspected to be suffering from a vascular disease. A“therapeutically effective amount” refers to that amount of atherapeutic agent that will have a beneficial affect, which may becurative or palliative, on the health and well-being of the patient withregard to the vascular disease with which the patient is known orsuspected to be afflicted. A therapeutically effective amount may beadministered as a single bolus, as intermittent bolus charges, as short,medium or long term sustained release formulations or as any combinationof these. As used herein, short-term sustained release refers to theadministration of a therapeutically effective amount of a therapeuticagent over a period from about several hours to about 3 days.Medium-term sustained release refers to administration of atherapeutically effective amount of a therapeutic agent over a periodfrom about 3 day to about 14 days and long-term refers to the deliveryof a therapeutically effective amount over any period in excess of about14 days.

As used herein, a “vascular disease” refers to a disease of the vessels,primarily arteries and veins, which transport blood to and from theheart, brain and peripheral organs such as, without limitation, thearms, legs, kidneys and liver. In particular “vascular disease” refersto the coronary arterial system, the carotid arterial system and theperipheral arterial system. The disease that may be treated is any thatis amenable to treatment with a therapeutic agent, either as the soletreatment protocol or as an adjunct to other procedures such as surgicalintervention. The disease may be, without limitation, atherosclerosis,vulnerable plaque, restenosis or peripheral arterial disease.

“Atherosclerosis” refers to the depositing of fatty substances,cholesterol, cellular waste products, calcium and fibrin on the innerlining or intima of an artery. Smooth muscle cell proliferation andlipid accumulation accompany the deposition process. In addition,inflammatory substances that tend to migrate to atherosclerotic regionsof an artery are thought to exacerbate the condition. The result of theaccumulation of substances on the intima is the formation of fibrous(atheromatous) plaques that occlude the lumen of the artery, a processcalled stenosis. When the stenosis becomes severe enough, the bloodsupply to the organ supplied by the particular artery is depletedresulting is strokes, if the afflicted artery is a carotid artery, heartattack if the artery is a coronary artery, or loss of organ function ifthe artery is peripheral.

“Restenosis” refers to the re-narrowing or blockage of an artery at ornear the site where angioplasty or another surgical procedure waspreviously performed to remove a stenosis. It is generally due to smoothmuscle cell proliferation and, at times, is accompanied by thrombosis.Prior to the advent of implantable stents to maintain the patency ofvessels opened by angioplasty, restenosis occurred in 40-50% of patientswithin 3 to 6 months of undergoing the procedure. Post-angioplastyrestenosis before stents was due primarily to smooth muscle cellproliferation. There were also issues of acute re-closure due tovasospasm, dissection, and thrombosis at the site of the procedure.Stents eliminated acute closure from vasospasm and greatly reducedcomplications from dissections. While the use of IIb-IIIa anti-plateletdrugs such as abciximab and epifabatide, which are anti-thrombotic,reduced the occurrence of post-procedure clotting (although stentplacement itself can initiate thrombosis). Stent placement sites arealso susceptible to restenosis due to abnormal tissue growth at the siteof implantation. This form of restenosis tends also to occur at 3 to 6months after stent placement but it is not affected by the use ofanti-clotting drugs. Thus, alternative therapies are continuously beingsought to mitigate, preferably eliminate, this type of restenosis. Drugeluting stents (DES) which release a variety of therapeutic agents atthe site of stent placement have been in use for some time. To datethese stents comprised delivery interfaces (lengths) that are less than40 mm in length and, in any event, have delivery interfaces that are notintended, and most often do not, contact the luminal surface of thevessel at the non-afflicted region at the periphery of the afflictedregion.

“Vulnerable plaque” refers to an atheromatous plaque that has thepotential of causing a thrombotic event and is usually characterized bya very thin wall separating it from the lumen of an artery. The thinnessof the wall renders the plaque susceptible to rupture. When the plaqueruptures, the inner core of usually lipid-rich plaque is exposed toblood, with the potential of causing a potentially fatal thromboticevent through adhesion and activation of platelets and plasma proteinsto components of the exposed plaque.

The phenomenon of “vulnerable plaque” has created new challenges inrecent years for the treatment of heart disease. Unlike occlusiveplaques that impede blood flow, vulnerable plaque develops within thearterial walls, but it often does so without the characteristicsubstantial narrowing of the arterial lumen which produces symptoms. Assuch, conventional methods for detecting heart disease, such as anangiogram, may not detect vulnerable plaque growth into the arterialwall.

The intrinsic histological features that may characterize a vulnerableplaque include increased lipid content, increased macrophage, foam celland T lymphocyte content, and reduced collagen and smooth muscle cell(SMC) content. This fibroatheroma type of vulnerable plaque is oftenreferred to as “soft,” having a large lipid pool of lipoproteinssurrounded by a fibrous cap. The fibrous cap contains mostly collagen,whose reduced concentration combined with macrophage-derived enzymedegradation can cause the fibrous cap of these lesions to rupture underunpredictable circumstances. When ruptured, the lipid core contents,thought to include tissue factor, contact the arterial bloodstream,causing a blood clot to form that can completely block the arteryresulting in an acute coronary syndrome (ACS) event. This type ofatherosclerosis is coined “vulnerable” because of unpredictable tendencyof the plaque to rupture. It is thought that hemodynamic and cardiacforces, which yield circumferential stress, shear stress, and flexionstress, may cause disruption of a fibroatheroma type of vulnerableplaque. These forces may rise as the result of simple movements, such asgetting out of bed in the morning, in addition to in vivo forces relatedto blood flow and the beating of the heart. It is thought that plaquevulnerability in fibroatheroma types is determined primarily by factorswhich include: (1) size and consistency of the lipid core; (2) thicknessof the fibrous cap covering the lipid core; and (3) inflammation andrepair within the fibrous cap.

“Thrombosis” refers to the formation or presence of a blood clot(thrombus) inside a blood vessel or chamber of the heart. A blood clotthat breaks off and travels to another part of the body is called anembolus. If a clot blocks a blood vessel that feeds the heart, it causesa heart attack. If a clot blocks a blood vessel that feeds to brain, itcauses a stroke.

Peripheral vascular diseases are generally caused by structural changesin blood vessels caused by such conditions as inflammation and tissuedamage. A subset of peripheral vascular disease is peripheral arterydisease (PAD). PAD is a condition that is similar to carotid andcoronary artery disease in that it is caused by the buildup of fattydeposits on the lining or intima of the artery walls. Just as blockageof the carotid artery restricts blood flow to the brain and blockage ofthe coronary artery restricts blood flow to the heart, blockage of theperipheral arteries can lead to restricted blood flow to the kidneys,stomach, arms, legs and feet.

Suitable therapeutic agents include, without limitation,anti-proliferative agents, anti-inflammatory agents, anti-neoplasticsand/or anti-mitotics, antiplatelet, anticoagulant, anti-fibrin, andanti-thrombin drugs, cytostatic or anti-proliferative agents,antibiotics, anti-allergic agents, antioxidants and other bioactiveagents known to those skilled in the art.

Suitable anti-proliferative agents include, without limitation,actinomycin D, or derivatives or analogs thereof, i.e., actinomycin D isalso known as dactinomycin, actinomycin IV, actinomycin I₁, actinomycinX₁, and actinomycin C₁. Antiproliferative agents can be naturalproteineous agents such as a cytotoxin or a synthetic molecule, alltaxoids such as taxols, docetaxel, and paclitaxel, paclitaxelderivatives, all olimus drugs such as macrolide antibiotics, rapamycin,everolimus, structural derivatives and functional analogues ofrapamycin, structural derivatives and functional analogues ofeverolimus, FKBP-12 mediated mTOR inhibitors, biolimus, perfenidone,prodrugs thereof, co-drugs thereof, and combinations thereof.Representative rapamycin derivatives and analogs include40-O-(2-hydroxyethyl)rapamycin (EVEROLIMUS®),40-O-(3-hydroxypropyl)rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazolylrapamycin, or40-epi-(N1-tetrazolyl)-rapamycin, prodrugs thereof, co-drugs thereof,and combinations thereof.

Suitable anti-inflammatory agents include, without limitation, steroidalanti-inflammatory agents, a nonsteroidal anti-inflammatory agent, or acombination thereof. In some embodiments, anti-inflammatory agentsinclude clobetasol, alclofenac, alclometasone dipropionate, algestoneacetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium,amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone,balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride,bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone,cliprofen, clobetasol propionate, clobetasone butyrate, clopirac,cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort,desonide, desoximetasone, dexamethasone dipropionate, diclofenacpotassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium,diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide,endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate,felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal,fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid,flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortinbutyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen,fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasolpropionate, halopredone acetate, ibufenac, ibuprofen, ibuprofenaluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacinsodium, indoprofen, indoxole, intrazole, isoflupredone acetate,isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam,loteprednol etabonate, meclofenamate sodium, meclofenamic acid,meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone,methylprednisolone suleptanate, momiflumate, nabumetone, naproxen,naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein,orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride,pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone,piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen,prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazolecitrate, rimexolone, romazarit, salcolex, salnacedin, salsalate,sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac,suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap,tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac,tixocortol pivalate, tolmetin, tolmetin sodium, triclonide,triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylicacid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus,pimecorlimus, prodrugs thereof, co-drugs thereof, and combinationsthereof. The anti-inflammatory agent may also be a biological inhibitorof proinflammatory signaling molecules including antibodies to suchbiological inflammatory signaling molecules.

Suitable antineoplastics and/or antimitotics include, withoutlimitation, paclitaxel, docetaxel, methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, andmitomycin.

Suitable antiplatelet, anticoagulant, antifibrin, and antithrombin drugsinclude, without limitation, sodium heparin, low molecular weightheparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,prostacyclin, prostacyclin dextran, D-phe-pro-arg-chloromethylketone,dipyridamole, glycoprotein Ilb/IIIa platelet membrane receptorantagonist antibody, recombinant hirudin and thrombin, thrombininhibitors such as Angiomax ä (Biogen, Inc., Cambridge, Mass.), calciumchannel blockers (such as nifedipine), colchicine, fish oil (omega3-fatty acid), histamine antagonists, lovastatin (an inhibitor ofHMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® fromMerck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies(such as those specific for Platelet-Derived Growth Factor (PDGF)receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandininhibitors, suramin, serotonin blockers, steroids, thioproteaseinhibitors, triazolopyrimidine (a PDGF antagonist), nitric oxide ornitric oxide donors, super oxide dismutases, super oxide dismutasemimetic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),estradiol, anticancer agents, dietary supplements such as variousvitamins, and a combination thereof. Examples of such cytostaticsubstance include angiopeptin, angiotensin converting enzyme inhibitorssuch as captopril (e.g. Capoten® and Capozide® from Bristol-Myers SquibbCo., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® andPrinzide® from Merck & Co., Inc., Whitehouse Station, N.J.). An exampleof an antiallergic agent is permirolast potassium. Other bioactivesubstances or agents that may be appropriate include alpha-interferon,and genetically engineered epithelial cells.

Suitable cytostatic or antiproliferative agents include, withoutlimitation, angiopeptin, angiotensin converting enzyme inhibitors suchas captopril, cilazapril or lisinopril, calcium channel blockers such asnifedipine; colchicine, fibroblast growth factor (FGF) antagonists; fishoil (ω-3-fatty acid); histamine antagonists; lovastatin, monoclonalantibodies such as, without limitation, those specific forPlatelet-Derived Growth Factor (PDGF) receptors; nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist) and nitric oxide.

Suitable antiallergic agents include, without limitation, permirolastpotassium. Other suitable bioactive agents include, without limitation,alpha-interferon, genetically engineered epithelial cells, dexamethasoneand its derivatives, rapamycin derivatives and analogs such as40-O-(2-hydroxyethyl)rapamycin (EVEROLIMUS®),40-O-(3-hydroxypropyl)rapamycin,40-O-[2-(2-hydroxyethoxy)]ethyl-rapamycin, and 40-O-tetrazolylrapamycin,synthetic inorganic and organic compounds, proteins and peptides,polysaccharides and other sugars, lipids, and DNA and RNA nucleic acidsequences having therapeutic, prophylactic or diagnostic activities,nucleic acid sequences include genes, antisense molecules which bind tocomplementary DNA to inhibit transcription, and ribozymes. Some otherexamples of suitable bioactive agents include antibodies, receptorligands, enzymes, adhesion peptides, blood clotting factors, inhibitorsor clot dissolving agents such as streptokinase and tissue plasminogenactivator, antigens for immunization, hormones and growth factors,oligonucleotides such as antisense oligonucleotides and ribozymes andretroviral vectors for use in gene therapy; antiviral agents; analgesicsand analgesic combinations; anorexics; antihelmintics; antiarthritics,antiasthmatic agents; anticonvulsants; antidepressants; antidiureticagents; antidiarrheals; antihistamines; antimigrain preparations;antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics;antipyretics; antispasmodics; anticholinergics; sympathomimetics;xanthine derivatives; cardiovascular preparations including calciumchannel blockers and beta-blockers such as pindolol and antiarrhythmics;antihypertensives; diuretics; vasodilators including general coronary;peripheral and cerebral; central nervous system stimulants; cough andcold preparations, including decongestants; hypnotics;immunosuppressives; muscle relaxants; parasympatholytics;psychostimulants; sedatives; tranquilizers; naturally derived orgenetically engineered lipoproteins; and restenoic reducing agents.

Preferred therapeutic agents include corticosteroids, everolimus,zotarolimus, sirolimus, sirolimus derivatives, paclitaxel,bisphosphonates, ApoA1, mutated ApoA1, ApoA1 milano, ApoA1 mimeticpeptides, ABC A1 agonists, anti-inflammatory agents, anti-proliferativeagents, anti-angiogenic agents, matrix metalloproteinase inhibitors andtissue inhibitors of metalloproteinases.

EXAMPLES

The embodiments of the present invention are further illustrated by thefollowing examples. The examples are provided for illustrative purposesonly and are not intended nor should they be construed as limiting thescope of this invention in any manner whatsoever.

Example 1

A composition was prepared by placing poly(L-lactide-co-ε-caprolactone)(0.12 g), chloroform (4.6848 g) and tricholoroethane (1.17 g) in atightly closed glass bottle and stirring at 250 rpm for 2 hours.Everolimus (0.0245 g) was then added to the reaction mixture and thereaction mixture was stirred at 500 rpm for an additional 2 minutes. Thefirst composition was applied onto the stent and dried to form adrug-polymer layer.

The composition was applied onto a stent by any conventional method, forexample, by spraying or dipping. A primer layer (e.g., the aboveformulation without the therapeutically active substance) can beoptionally applied on the surface of the bare stent prior to theapplication of the drug-polymer layer. The drug to polymer wt/wt ratiois 1:5. The drug dose is about 100 microgram/cm². The drug reservoirlayer coating thickness is 6 um.

Example 2

A composition was prepared by placing poly(L-lactide-co-ε-caprolactone)(0.12 g), chloroform (4.67 g) and tricholoroethane (1.17 g) in a tightlyclosed glass bottle and stirring at 250 rpm for 2 hours. Everolimus(0.0408 g) was then added to the reaction mixture and the reactionmixture was stirred at 500 rpm for an additional 2 minutes. The firstcomposition was applied onto the stent and dried to form a drug-polymerlayer.

The composition was applied onto a stent by any conventional method, forexample, by spraying or dipping. A primer layer (e.g., the aboveformulation without the therapeutically active substance) can beoptionally applied on the surface of the bare stent prior to theapplication of the drug-polymer layer. The drug to polymer wt/wt ratiois 1:3. The drug dose is about 100 microgram/cm². The drug reservoirlayer coating thickness is 4 um.

Example 3

A composition was prepared by placing poly(L-lactide-co-trimethylenecarbonate) (0.06 g) and tricholoroethane (2.928 g) in a tightly closedglass bottle and stirring 250 rpm for 2 hours. Everolimus (0.01224 g)was then added to the reaction mixture and the reaction mixture wasstirred at 500 rpm for an additional 2 minutes. The first compositionwas applied onto the stent and dried to form a drug-polymer layer.

The composition was applied onto a stent by any conventional method, forexample, by spraying or dipping. A primer layer (e.g., the aboveformulation without the therapeutically active substance) can beoptionally applied on the surface of the bare stent prior to theapplication of the drug-polymer layer. The drug to polymer wt/wt ratiois 1:5. The drug dose is about 100 microgram/cm². The drug reservoirlayer coating thickness is 6 um.

Example 4

A composition was prepared by placing poly(L-lactide-co-trimethylenecarbonate) (0.06 g) and tricholoroethane (2.928 g) in a tightly closedglass bottle and stirring at 250 rpm for 2 hours. Everolimus (0.01224 g)was then added to the reaction mixture and the reaction mixture wasstirred at 500 rpm for an additional 2 minutes. The first compositionwas applied onto the stent and dried to form a drug-polymer layer.

The composition was applied onto a stent by any conventional method, forexample, by spraying or dipping. A primer layer (e.g., the aboveformulation without the therapeutically active substance) can beoptionally applied on the surface of the bare stent prior to theapplication of the drug-polymer layer. The drug to polymer wt/wt ratiois 1:5. The drug dose is about 50 microgram/cm². The drug reservoirlayer coating thickness is 6 um.

Example 5

A composition was prepared by placing poly(L-lactide-co-ε-caprolactone)(0.12 g), chloroform (4.6848 g) and tricholoroethane (1.17 g) in atightly closed glass bottle and stirring at 250 rpm for 2 hours.Phosphoryl choline (0.2 g) in methanol (2.44 g) and dimethylacetamide(2.44 g) was added to the reaction mixture and mixture further stirredfor 2 hours. Everolimus (0.0444 g) was then added to the reactionmixture and the reaction mixture was stirred at 500 rpm for anadditional 2 minutes. The first composition was applied onto the stentand dried to form a drug-polymer layer.

The composition was applied onto a stent by any conventional method, forexample, by spraying or dipping. A primer layer (e.g., the aboveformulation without the therapeutically active substance) can beoptionally applied on the surface of the bare stent prior to theapplication of the drug-polymer layer. The drug to polymer wt/wt ratiois 1:5. The drug dose is about 100 microgram/cm². The drug reservoirlayer coating thickness is 6 um.

Example 6

A composition was prepared by placing poly(L-lactide-co-trimethylenecarbonate) (0.12 g) chloroform (4.6848 g) and tricholoroethane (1.17 g)in a tightly closed glass bottle and stirring at 250 rpm for 2 hours.Phosphorylcholine (0.2 g) in methanol (2.44 g) and dimethylacetamide(2.44 g) was added to the reaction mixture and mixture further stirredfor 2 hours. Everolimus (0.0444 g) was then added to the reactionmixture and the reaction mixture was stirred at 500 rpm for anadditional 2 minutes. The first composition was applied onto the stentand dried to form a drug-polymer layer.

The composition was applied onto a stent by any conventional method, forexample, by spraying or dipping. A primer layer (e.g., the aboveformulation without the therapeutically active substance) can beoptionally applied on the surface of the bare stent prior to theapplication of the drug-polymer layer. The drug to polymer wt/wt ratiois 1:5. The drug dose is about 100 microgram/cm². The drug reservoirlayer coating thickness is 6 um.

Example 7

A composition was prepared by placing poly(L-lactide-co-ε-caprolactone)(0.2 g), acetone (8 g) and methylisobutylketone (2 g) in a tightlyclosed glass bottle and stirring at 560 rpm for 2 hours. cRGD (0.4 g)was added to the reaction mixture and mixture further stirred for 2hours. Everolimus (0.06 g) was then added to the reaction mixture andthe reaction mixture was stirred at 500 rpm for an additional 2 minutes.The first composition was applied onto the stent and dried to form adrug-polymer layer.

The composition was applied onto a stent by any conventional method, forexample, by spraying or dipping. A primer layer (e.g., the aboveformulation without the therapeutically active substance) can beoptionally applied on the surface of the bare stent prior to theapplication of the drug-polymer layer. The drug to polymer wt/wt ratiois 1:5. The drug dose is about 100 microgram/cm². The drug reservoirlayer coating thickness is 56 um.

Example 8

A composition was prepared by placing poly(L-lactide-co-ε-caprolactone)(0.2 g), acetone (8 g) and methylisobutylketone (2 g) in a tightlyclosed glass bottle and stirring at 560 rpm for 2 hours. RGD (0.4 g) wasadded to the reaction mixture and mixture further stirred for 2 hours.Everolimus (0.06 g) was then added to the reaction mixture and thereaction mixture was stirred at 500 rpm for an additional 2 minutes. Thefirst composition was applied onto the stent and dried to form adrug-polymer layer.

The composition was applied onto a stent by any conventional method, forexample, by spraying or dipping. A primer layer (e.g., the aboveformulation without the therapeutically active substance) can beoptionally applied on the surface of the bare stent prior to theapplication of the drug-polymer layer. The drug to polymer wt/wt ratiois 1:5. The drug dose is about 100 microgram/cm². The drug reservoirlayer coating thickness is 56 um.

Example 9

A composition was prepared by placing poly(L-lactide-co-trimethylenecarbonate) (0.2 g), acetone (8 g) and methylisobutylketone (2 g) in atightly closed glass bottle and stirring at 560 rpm for 2 hours. cRGD(0.4 g) was added to the reaction mixture and mixture further stirredfor 2 hours. Everolimus (0.06 g) was then added to the reaction mixtureand the reaction mixture was stirred at 500 rpm for an additional 2minutes. The first composition was applied onto the stent and dried toform a drug-polymer layer.

The composition was applied onto a stent by any conventional method, forexample, by spraying or dipping. A primer layer (e.g., the aboveformulation without the therapeutically active substance) can beoptionally applied on the surface of the bare stent prior to theapplication of the drug-polymer layer. The drug to polymer wt/wt ratiois 1:5. The drug dose is about 100 microgram/cm². The drug reservoirlayer coating thickness is 56 um.

Example 10

A composition was prepared by placing poly(L-lactide-co-trimethylenecarbonate) (0.2 g), acetone (8 g) and methylisobutylketone (2 g) in atightly closed glass bottle and stirring at 560 rpm for 2 hours. RGD(0.4 g) was added to the reaction mixture and mixture further stirredfor 2 hours. Everolimus (0.06 g) was then added to the reaction mixtureand the reaction mixture was stirred at 500 rpm for an additional 2minutes. The first composition was applied onto the stent and dried toform a drug-polymer layer.

The composition was applied onto a stent by any conventional method, forexample, by spraying or dipping. A primer layer (e.g., the aboveformulation without the therapeutically active substance) can beoptionally applied on the surface of the bare stent prior to theapplication of the drug-polymer layer. The drug to polymer wt/wt ratiois 1:5. The drug dose is about 100 microgram/cm². The drug reservoirlayer coating thickness is 56 um.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

The present invention also includes the following embodiments.

1. A method of treating a vascular disease, comprising:

deploying in the vasculature of a patient in need thereof an implantablemedical device, wherein the device comprises:

a device body;

an optional primer layer disposed over the device body; and

a drug reservoir layer disposed over the device body or the primerlayer, if opted,

wherein the drug reservoir layer comprises:

-   -   a high molecular weight copolymer of lactic acid, L-lactide,        D,L-lactide, meso lactide or glycolic acid with ε-caprolactone        or trimethylene carbonate, at least a portion of which is        substituted with a pendant hemocompatible and/or prohealing        moiety;    -   or,    -   a blend of a high molecular weight copolymer of lactic acid,        L-lactide, D,L-lactide, meso-lactide or glycolic acid with        ε-caprolactone or trimethylene carbonate and a low molecular        weight copolymer of lactic acid, L-lactide, D,L-lactide,        meso-lactide, or glycolic acid with ε-caprolactone or        trimethylene carbonate at least a portion of which is        substituted with a pendant hemocompatible and/or prohealing        moiety;    -   or,    -   a high molecular weight copolymer of lactic acid, L-lactide,        D,L-lactide, meso-lactide or glycolic acid with ε-caprolactone        or trimethylene carbonate; and,    -   one or more therapeutic agents, wherein:        -   if the drug reservoir layer comprises a high molecular            weight copolymer of lactic acid, L-lactide, D,L-lactide,            meso-lactide or glycolic acid with ε-caprolactone or            trimethylene carbonate, the implantable medical device            further has a topcoat layer comprising a low molecular            weight copolymer of lactic acid, L-lactide, D,L-lactide,            meso-lactide or glycolic acid with ε-caprolactone or            trimethylene carbonate at least a portion of which is            substituted with a pendant hemocompatible and/or prohealing            moiety.            2. The method of embodiment 1, wherein the device is a            stent.            3. The method of embodiment 1, wherein the hemocompatible            and/or prohealing moiety comprises a polyhydroxyalkyl.            4. The method of embodiment 1, wherein the drug reservoir            layer or the topcoat layer comprising a polyhydroxyalkyl            moiety has the formula:

wherein:

L comprises a Linker;

m is from about 0.01 to about 0.99;

n is from about 0.99 to about 0.01;

n+m=1; and

p is an integer from 0 to 200.

5. The method of embodiment 4, wherein the m is from about 0.5 to about0.8.6. The method of embodiment 5, wherein the m is from about 0.65 to about0.75.7. The method of embodiment 3, wherein the polyhydroxyalkyl is selectedfrom the group consisting of glycerol, sorbitol, mannitol, a glycol, apolyalkylglycol and a polyglycol.8. The method of embodiment 1, wherein the hemocompatible and/orprohealing moiety comprises a peptide.9. The method of embodiment 1, wherein the drug reservoir layer or thetopcoat layer comprising a peptide moiety has the formula:

wherein:

L comprises a Linker; and,

m is from about 0.01 to about 0.99;

n is from about 0.99 to about 0.01; and

n+m=1

10. The method of embodiment 9, wherein the m is from about 0.5 to about0.8.11. The method of embodiment 10, wherein the m is from about 0.65 toabout 0.75.12. The method of embodiment 8, wherein the peptide is selected from thegroup consisting of RGD, cyclic RGD (cRGD) and an RGD mimetic.13. The method of embodiment 1, wherein the hemocompatible and/orprohealing moiety comprises a phosphorylcholine.14. The method of embodiment 1, wherein the drug reservoir layer or thetopcoat layer comprising a phosphorylcholine moiety has the formula:

wherein:

L comprises a Linker; and

m is from about 0.01 to about 0.99;

n is from about 0.99 to about 0.01; and

n+m=1.

15. The method of embodiment 14, wherein the m is from about 0.5 toabout 0.8.16. The method of embodiment 15, wherein the m is from about 0.65 toabout 0.75.17. The method of embodiment 1, wherein the drug reservoir layer polymerhas a molecular weight from about 50,000 to about 500,000 Daltons.18. The method of embodiment 1, wherein the drug reservoir layer has acoating thickness from about 1 um to about 10 um.19. The method of embodiment 1, wherein the drug to polymer wt/wt ratioin the drug reservoir layer is from about 1.0:0.5 to about 1.0:10.0.20. The method of embodiment 1, wherein the drug dose is from about5-200 microgram/cm² to about 20-100 microgram/cm².21. The method of embodiment 1, wherein the vascular disease isatherosclerosis.22. The method of embodiment 1, wherein the vascular disease isrestenosis.23. The method of embodiment 1, wherein the vascular disease isvulnerable plaque.24. The method of embodiment 1, wherein the vascular disease isperipheral vascular disease.25. The method of embodiment 21, wherein the vascular disease is latestent thrombosis.

What is claimed is:
 1. A method of treating a vascular disease,comprising: deploying in the vasculature of a patient in need thereof animplantable medical device, wherein the device comprises: a device body;an optional primer layer disposed over the device body; and a drugreservoir layer disposed over the device body or the primer layer, ifopted, wherein the drug reservoir layer comprises: a high molecularweight copolymer of lactic acid, L-lactide, D,L-lactide, meso-lactide orglycolic acid with ε-caprolactone or trimethylene carbonate, at least aportion of which is substituted with a pendant hemocompatible and/orprohealing moiety; or, a blend of a high molecular weight copolymer oflactic acid, L-lactide, D,L-lactide, meso-lactide or glycolic acid withε-caprolactone or trimethylene carbonate and a low molecular weightcopolymer of lactic acid, L-lactide, D,L-lactide, meso-lactide, orglycolic acid with ε-caprolactone or trimethylene carbonate at least aportion of which is substituted with a pendant hemocompatible and/orprohealing moiety; or, a high molecular weight copolymer of lactic acid,L-lactide, D,L-lactide, meso-lactide or glycolic acid withε-caprolactone or trimethylene carbonate; and, one or more therapeuticagents, wherein: if the drug reservoir layer comprises a high molecularweight copolymer of lactic acid, L-lactide, D,L-lactide, meso-lactide orglycolic acid with ε-caprolactone or trimethylene carbonate, theimplantable medical device further has a topcoat layer comprising a lowmolecular weight copolymer of lactic acid, L-lactide, D,L-lactide,meso-lactide or glycolic acid with ε-caprolactone or trimethylenecarbonate at least a portion of which is substituted with a pendanthemocompatible and/or prohealing moiety.
 2. The method of claim 1,wherein the device is a stent.
 3. The method of claim 1, wherein thehemocompatible and/or prohealing moiety comprises a polyhydroxyalkyl. 4.The method of claim 1, wherein the drug reservoir layer or the topcoatlayer comprising a polyhydroxyalkyl moiety having the formula:

wherein: L comprises a Linker; m is from about 0.01 to about 0.99; n isfrom about 0.99 to about 0.01; n+m=1; and p is an integer from 0 to 200.5. The method of claim 4, wherein the m is from about 0.5 to about 0.8.6. The method of claim 5, wherein the m is from about 0.65 to about0.75.
 7. The method of claim 3, wherein the polyhydroxyalkyl is selectedfrom the group consisting of glycerol, sorbitol, mannitol, a glycol, apolyalkylglycol and a polyglycol.
 8. The method of claim 1, wherein thehemocompatible and/or prohealing moiety comprises a peptide.
 9. Themethod of claim 8, wherein the peptide is selected from the groupconsisting of RGD, cyclic RGD (cRGD) and an RGD mimetic.
 10. The methodof claim 1, wherein the hemocompatible and/or prohealing moietycomprises a phosphorylcholine.
 11. The method of claim 1, wherein thedrug reservoir layer or the topcoat layer comprising a phosphorylcholinemoiety has the formula:

wherein: L comprises a Linker; and m is from about 0.01 to about 0.99; nis from about 0.99 to about 0.01; and n+m=1.
 12. The method of claim 11,wherein the m is from about 0.5 to about 0.8.
 13. The method of claim11, wherein the m is from about 0.65 to about 0.75.
 14. The method ofclaim 1, wherein the drug reservoir layer polymer has a molecular weightfrom about 50,000 to about 500,000 Daltons.
 15. The method of claim 1,wherein the drug reservoir layer has a coating thickness from about 1 umto about 10 um.
 16. The method of claim 1, wherein the drug to polymerwt/wt ratio in the drug reservoir layer is from about 1.0:0.5 to about1.0:10.0.
 17. The method of claim 1, wherein the drug dose is from about5-200 microgram/cm² to about 20-100 microgram/cm².
 18. The method ofclaim 1, wherein the vascular disease is atherosclerosis, restenosis,vulnerable plaque, and peripheral vascular disease.
 19. The method ofclaim 18, wherein the vascular disease is late stent thrombosis.